Amikacin combined with fosfomycin for treatment of neonatal sepsis in the setting of highly prevalent antimicrobial resistance

Christopher A. Darlow, Fernando Docobo-Perez, Nicola Farrington, Adam Johnson, Laura McEntee, Jennifer Unsworth, Ana Jimenez-Valverde, Silke Gastine, Ruwanthi Kolamunnage-Dona, Renata M.A. de Costa, Sally Ellis, François Franceschi, Joseph F. Standing, Mike Sharland, Michael Neely, Laura Piddock, Shampa Das, William Hope

Research output: Contribution to journalArticlepeer-review

Abstract

Antimicrobial resistance (particularly through extended-spectrum b-lactamase and aminoglycoside-modifying enzyme production) in neonatal sepsis is a global problem, particularly in low- and middle-income countries, with significant mortality rates. High rates of resistance are reported for the current WHO-recommended first-line antibiotic regimen for neonatal sepsis, i.e., ampicillin and gentamicin. We assessed the utility of fosfomycin and amikacin as a potential alternative regimen to be used in settings of increasingly prevalent antimicrobial resistance. The combination was studied in a 16-arm dose-ranged hollow-fiber infection model (HFIM) experiment. The combination of amikacin and fosfomycin enhanced bactericidal activity and prevented the emergence of resistance, compared to monotherapy with either antibiotic. Modeling of the experimental quantitative outputs and data from checkerboard assays indicated synergy. We further assessed the combination regimen at clinically relevant doses in the HFIM with nine Enterobacterales strains with high fosfomycin and amikacin MICs and demonstrated successful kill to sterilization for 6/9 strains. From these data, we propose a novel combination breakpoint threshold for microbiological success for this antimicrobial combination against Enterobacterales strains, i.e., MICF × MICA , 256 (where MICF and MICA are the fosfomycin and amikacin MICs, respectively). Monte Carlo simulations predict that a standard fosfomycin-amikacin neonatal regimen would achieve .99% probability of pharmacodynamic success for strains with MICs below this threshold. We conclude that the combination of fosfomycin with amikacin is a viable regimen for the empirical treatment of neonatal sepsis and is suitable for further clinical assessment in a randomized controlled trial.

Original languageEnglish
Article numbere00293-21
JournalAntimicrobial Agents and Chemotherapy
Volume65
Issue number7
DOIs
Publication statusPublished - Jul 2021
Externally publishedYes

Keywords

  • Amikacin
  • Aminoglycosides
  • Antimicrobial resistance
  • Combination antibiotics
  • Fosfomycin
  • Hollow fiber
  • Mathematical modelling
  • Neonatal sepsis
  • Pharmacodynamics
  • Synergy

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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